10RCSummary for 10RC
| Entry DOI | 10.2210/pdb10rc/pdb |
| Related | 10RA 10RB |
| Descriptor | NAD(+) hydrolase SARM1, GLYCEROL, 1-[(2R,3R,4S,5R)-5-({[(S)-{[(S)-{[(2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy}(hydroxy)phosphoryl]oxy}(hydroxy)phosphoryl]oxy}methyl)-3,4-dihydroxyoxolan-2-yl]-4-{(6P)-7-{[2-(dimethylamino)ethyl]amino}-6-[6-fluoro-4-(pyrimidin-2-yl)-1H-indol-2-yl]-1-methyl-1H-imidazo[4,5-c]pyridin-2-yl}pyridin-1-ium (non-preferred name), ... (4 entities in total) |
| Functional Keywords | hydrolase, inhibitor, adduct, nad |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 34602.99 |
| Authors | Dementiev, A.,Johnson, Z.L.,Olland, A.M. (deposition date: 2026-02-02, release date: 2026-04-22, Last modification date: 2026-04-29) |
| Primary citation | Albanese, S.K.,Hopkins, B.E.,Olland, A.M.,Fairman, A.,Shaikh, N.,Feng, S.,Thakkar, M.,Verras, A.,Dementiev, A.,Walkup 4th, W.G.,Atsriku, C.,Srinivas, H.D.,Allen, W.,Ashraf, K.,Bos, P.H.,Hsiao, P.,Kroeck, K.,Liu, Z.,Nagarajan, A.,Szlenk, C.T.,Svensson, M.,Johnson, Z.L.,Kapilashrami, K.,Rubino, S.,Kaplan, A.,Levinson, A.M. Structure-Based Discovery of Imidazo[4,5- c ]pyridine SARM1 Modulators Showing Paradoxical Activation. J.Med.Chem., 69:9521-9536, 2026 Cited by PubMed Abstract: Sterile Alpha and TIR Motif Containing 1 (SARM1) is an NAD hydrolase enzyme implicated in neurological diseases with prominent axonopathies. A reported method for SARM1 inhibition involves the design of small molecules bearing reactive heterocyclic warheads, which intercept the hydrolysis of NAD in the active site of SARM1 and subsequently inhibit enzymatic function of the TIR domain. Herein, we describe the discovery of a series of bicyclic SARM1 inhibitors, initially identified via a unique workflow for free-energy perturbation (FEP+) simulations. Subsequent hit expansion efforts identified potent and cell-active inhibitors with slow off-rates, which impart a unique conformational state of W662 in the SARM1 catalytic site, as assessed via X-ray crystallography. Finally, we discuss an identified liability associated with substrate-based SARM1 inhibitors such as , whereby insufficient target engagement results in an increase in biomarkers of neurodegeneration at low doses and exacerbates neuronal degeneration and cell death . PubMed: 41948869DOI: 10.1021/acs.jmedchem.6c00352 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.9 Å) |
Structure validation
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